Design, Synthesis, and In Vitro Anti-Tumor Activities of 1,2,3-triazole-tetraethylene Glycol Tethered Heteronuclear Bis-Schiff Base Derivatives of Isatin

Article abstract of DOI:10.1002/jhet.3341

We report herein the design, synthesis, and in vitro anti-tumor activities of a series of 1,2,3-triazole-tetraethylene glycol tethered heteronuclear bis-Schiff base derivatives of isatin. Our results indicated that all the synthesized bis-Schiff bases except 9e showed considerable in vitro anticancer activities against HepG2, Hela, HCT-116, A549, and MCF-7 human cancer cell lines with IC₅₀ in a range of 9.79–48.75?μM and were more potent than etoposide against Hela, HCT-116, and A549 cell lines. In particular, the most potent bis-Schiff base 9g (IC₅₀: 9.79–29.64?μg/mL) was highly active against the five cancer cell lines tested, could act as a lead for further optimization.

Full text of DOI:10.1002/jhet.3341

Month 2018
Design, Synthesis, and In Vitro Anti-Tumor Activities of 1,2,3-triazole-
tetraethylene Glycol Tethered Heteronuclear Bis-Schiff Base Derivatives
of Isatin
a
b
a
a
a
Ruo Wang, * Xueyang Yin, Yaohuan Zhang, Tesen Zhang, and Weixiong Shi
a
College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, People’s Republic of China
b
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, School of Chemistry
and Molecular Engineering, East China Normal University, Shanghai 20024 1, China
*
E-mail: wangruo1201@gmail.com
Received June 10, 2018
DOI 10.1002/jhet.3341
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
We report herein the design, synthesis, and in vitro anti-tumor activities of a series of 1,2,3-triazole-
tetraethylene glycol tethered heteronuclear bis-Schiff base derivatives of isatin. Our results indicated that
all the synthesized bis-Schiff bases except 9e showed considerable in vitro anticancer activities against
HepG2, Hela, HCT-116, A549, and MCF-7 human cancer cell lines with IC50 in a range of 9.79–
4
8.75 μM and were more potent than etoposide against Hela, HCT-116, and A549 cell lines. In particular,
the most potent bis-Schiff base 9g (IC50: 9.79–29.64 μg/mL) was highly active against the five cancer cell
lines tested, could act as a lead for further optimization.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
Organization has estimated that more than 10 million of
new cases and 8 million cancer-related deaths occurred
annually, and the numbers of new cases are expected to
rise by around 70% in the next two decades [3], creating
an urgent need to develop novel anticancer agents.
Isatin and triazole derivatives, exhibit a variety of
pharmacological properties such as anti-bacterial [4], anti-
HIV [5,6], antimalarial [7,8], anti-tubercular [9,10], and
anticancer [11,12] activities, occupy an important
position in the development of new drugs. Moreover,
some isatin-based or triazole-based drugs like
carboxyamidotriazole and sunitinib (Fig. 1) have already
Cancer, which is a type of disease where cells grow
beyond their usual boundaries that can then invade
adjoining parts of the body and/or spread to other organs,
is an ancient disease that has been a scourge of humanity
for thousands of years [1,2]. Cancer can affect almost all
part of the body and has many anatomic and molecular
subtypes, and lung, prostate, colorectal, stomach, and liver
cancer are the most common types of cancer in men, while
breast, colorectal, lung, cervix, and stomach cancer are the
most common among women [3]. The World Health
©
2018 Wiley Periodicals, Inc.

R. Wang, X. Yin, Y. Zhang, T. Zhang, and W. Shi
Vol 000
Figure 1. Chemical structures of carboxyamidotriazole and sunitinib. [Color figure can be viewed at wileyonlinelibrary.com]
been used in clinical practice or under clinical trials for the
treatment of cancers. Therefore, hybridization of isatin and
triazole may provide more effective anticancer candidates.
Recently, isatin dimers were found to possess promising
anticancer potential and have been widely studied [13–16].
The structure–activity relationship (SAR) revealed that the
linker and the noncovalent interactions are crucial for the
biological activities of isatin dimers [17–20]. 1,2,3-
Triazole and tetraethylene glycol can exert various
noncovalent interactions, so the isatin dimers tethered
through 1,2,3-triazole-tetraethylene glycol may have
promising anticancer activity.
As a continuous program to search new anticancer
candidates, a series of novel 1,2,3-triazole-tetraethylene
glycol tethered heteronuclear bis-Schiff base derivatives
of isatin were designed, synthesized, and evaluated for
their in vitro anticancer activity against HepG2 (liver
carcinoma), Hela (cervical cancer), HCT-116 (colon
cancer), A549 (lung adenocarcinoma), and MCF-7
RESULTS AND DISCUSSION
Detailed route for synthesis of 1,2,3-triazole-
tetraethylene glycol tethered heteronuclear bis-Schiff base
derivatives of isatin 9a–j was depicted in Scheme 1.
Condensations of C-5 substituted isatin
1
with
methoxyamine or ethoxyamine hydrochloride yielded the
intermediates 2. Introduction of tosyl group into
tetraethylene glycol 3 with triethylamine as base gave
intermediate 4, which was then reacted with alkyloximine
isatins 2 in presence of potassium carbonate (K CO )
2
3
generated the intermediate 5. The precursor 6 was
achieved by treatment of intermediate 5 with sodium
azide. Alkylation of isatins 7a–c with propargyl
bromide in presence of K CO afforded intermediate 8
2
3
that was consequently utilized for the synthesis of
1,2,3-triazole-tetraethylene glycol tethered heteronuclear
bis-Schiff bases of isatin 9a–e via click chemistry with
copper acetate (Cu (OAc)2) as catalyst. Finally,
condensations of targets 9a–e with the requested amine
hydrochlorides in the presence of sodium bicarbonate
provided targets 9f–j [15].
(breast cancer) human cancer cell lines in this paper.
The illustration of the design strategy is depicted in
Figure 2.
All
1,2,3-triazole-tetraethylene
glycol
tethered
heteronuclear bis-Schiff base derivatives of isatin 9a–j
were evaluated for their in vitro anticancer activities
against human cancer cell lines, including HepG2 (liver
carcinoma), Hela (cervical cancer), HCT-116 (colon
cancer), A549 (lung adenocarcinoma), and MCF-7 (breast
cancer) by SRB assay, and the results were presented in
Table 1. IC50 values were presented as the concentration
of drug inhibition 50% cell growth and determined by at
least three separate tests and reported.
It can be seen from Table 1 that all bis-Schiff bases of
isatin 9a–j except 9e showed considerable in vitro
anticancer activities against HepG2, Hela, HCT-116,
A549, and MCF-7 human cancer cell lines with IC50 in a
range of 9.79–48.75 μM. In spite of all, derivatives
were less active than the reference etoposide against
HepG2 and MCF-7, but all of them except 9e were
more potent than etoposide against Hela, HCT-116, and
A549 cell lines.
Figure 2. Design strategy of 1,2,3-triazole-tetraethylene glycol tethered
heteronuclear bis-Schiff base derivatives of isatin. [Color figure can be
viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Design, Synthesis, and In Vitro Anti-Tumor Activities of 1,2,3-Triazole-
tetraethylene Glycol Tethered Heteronuclear Bis-Schiff Base Derivatives of Isatin
Scheme 1. Synthesis of 1,2,3-triazole-tetraethylene glycol tethered heteronuclear bis-Schiff base derivatives of isatin 9a–j.
Table 1
The SAR revealed that the anticancer activity was
influenced greatly by the substituents at both C-3
position and C-5 position of isatin moiety: bis-Schiff
bases with bis-imines at C-3 position of the two isatin
motifs were more potent than the corresponding analogs
with mono-imine or ketone, and the relative contribution
order of the substituents to the activity was –NOH > –
NOEt > –NOMe > –O, suggesting installation of
imines could enhance the activity and hydrogen bond
donor at this position preferred; introduction of halogen
Anticancer activities of bis-Schiff base derivatives of isatin 9a–j.
IC50 (μM)
Compd.
HepG2 Hela
HCT-116 A549
MCF-7
9
9
9
9
9
9
9
9
9
9
a
b
c
d
e
f
g
h
i
31.34
19.83
48.75
23.12
36.99 >50
27.27
9.79
29.97
35.89
28.87
38.97
29.36
18.75
28.77
21.36
42.25
33.31
15.39
37.35
19.31
18.75
27.31
29.35
30.59
33.17
21.43
21.82
29.64
25.66
27.69
29.36
48.53
35.67
47.59
40.36
>50
26.67
19.38
37.59
31.37
27.39
8.76
21.66
40.53
29.97
28.67
-F at C-5 position was detrimental to the activity
18.36
35.46
21.21
19.97
generally. In particular, the most potent 9g (IC : 9.79–
50
29.64 μg/mL) was highly active against all the tested
five cell lines, could act as a starting point for further
optimization.
j
Etoposide
2.86 >50
>50
>50
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Wang, X. Yin, Y. Zhang, T. Zhang, and W. Shi
CONCLUSIONS t, ─CH ─), 3.66 (2H, t, ─CH ─), 3.72 (2H, t, ─CH ─),
series of novel 1,2,3-triazole- and ─CH ─), 4.96 (2H, s, ─CH ─), 7.03 (1H, d,
Vol 000
2
2
2
3
.83 (2H, t, ─CH ─), 4.44–4.52 (4H, m, NOCH CH
2
2
3
In summary,
a
2
2
tetraethylene glycol tethered bis-Schiff bases of isatin
were designed, synthesized, and evaluated for their
in vitro anti-tumor activities in this paper. All the
synthesized bis-Schiff bases of isatin except 9e showed
considerable activities, especially, the most active 9g was
highly active against all the tested five cell lines, warrant
further optimization. Moreover, SAR was also discussed,
and the enriched SAR may pave the way for further
investigations.
Ar─H), 7.12 (1H, t, Ar─H), 7.20 (1H, d, Ar─H), 7.26
(1H, d, Ar─H), 7.57 (1H, d, Ar─H), 7.68 (1H, t, Ar─H),
7.72 (1H, s, Ar─H), 8.10 (1H, s, triazole-H). ESI-MS
+
m/z: 613 [M + Na] . Elemental Anal. Calcd (%) for
C H N O : C, 61.01; H, 5.80; N, 14.23; found: C,
30 34 6 7
60.83; H, 5.59; N, 14.07.
5-Fluoro-1-((1-(2-(2-(2-(2-(3-(methoxyimino)-5-methyl-2-
oxoindolin-1-yl)ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-
yl)methyl)indoline-2,3-dione (9c).
Yellow solid, yield:
1
5
4%. H NMR (400 MHz, DMSO-d ) 2.29 (3H, s, CH ),
6
3
3
3
.38–3.43 (6H, m, 3 × ─CH ─), 3.47 (2H, t, ─CH ─),
2
2
EXPERIMENTAL SECTION
.67 (2H, t, ─CH ─), 3.74 (2H, t, ─CH ─), 3.84 (2H, t,
2
2
─
CH ─), 4.21 (3H, s, NOMe), 4.45 (2H, t, ─CH ─),
2
2
The general procedure for preparing targets 9a–j. The
intermediates 6 and 8 were synthesized according to the
well-established procedures [18,19]. The mixture of
intermediates 6 (10 mmol), 8 (10 mmol), and Cu (OAc)2
4.98 (2H, s, ─CH ─), 7.06 (1H, d, Ar─H), 7.24–7.27
(2H, m, Ar─H), 7.44 (1H, d, Ar─H), 7.50 (1H, t,
Ar─H), 7.70 (1H, s, Ar─H), 8.10 (1H, s, triazole-H).
2
+
ESI-MS m/z: 617 [M + Na] . Elemental Anal. Calcd (%)
(0.5 mmol) in dimethylformamide (10 mL) were stirred
for C H FN O : C, 58.58; H, 5.26; N, 14.13; found: C,
30
31
6 7
at room temperature for 12 h, and then removal of the
solvent under reduced pressure. The residue was purified
by silica gel chromatography eluted with PE:EA = 1:1 to
give the desired bis-Schiff bases of isatin 9a–e. To a
mixture of bis-Schiff bases of isatin 9a–e (1 mmol) and
NaHCO3 (6 mmol) in water (10 mL) and MeOH
58.29; H, 5.11; N, 13.87.
1-((1-(2-(2-(2-(2-(3-(Ethoxyimino)-5-methyl-2-oxoindolin-1-
yl)ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-5-
fluoroindoline-2,3-dione (9d).
Yellow solid, yield: 37%.
NMR (400 MHz, DMSO-d6) 1.39 (3H, t,
NOCH CH ), 2.29 (3H, s, CH ), 3.38–3.44 (6H, m,
1
H
2
3
3
3
× ─CH ─), 3.48 (2H, t, ─CH ─), 3.62 (2H, t,
2
2
(50 mL), the requested amine hydrochloride (5 mmol)
─
CH ─), 3.74 (2H, t, ─CH ─), 3.84 (2H, t, ─CH ─),
2
2
2
was added. The mixture was stirred at 50°C for 12 h.
After cooling to room temperature, the mixture was
extracted with EA (20 mL × 2). The combined organic
4
.42–4.50 (4H, m, NOCH CH and ─CH ─), 4.97 (2H,
2
3
2
s, ─CH ─), 7.04 (1H, t, Ar─H), 7.15–7.28 (3H, m,
2
Ar─H), 7.46–7.50 (1H, m, Ar─H), 7.65–7.71 (1H, m,
layers were washed with H O (50 mL × 2) and brine
2
Ar─H), 8.11 (1H, s, triazole-H). ESI-MS m/z: 631
(
50 mL) in sequence and dried over anhydrous Na SO .
2 4
+
[M
+
Na] . Elemental Anal. Calcd (%) for
After filtration, the filtrate was concentrated under
reduced pressure to give a residue that was purified by
silica gel chromatography eluted with PE:EA = 1:1 to
give the desired bis-Schiff bases of isatin 9f–j.
C H FN O : C, 59.20; H, 5.47; N, 13.81; found: C,
30
33
6 7
5
8.95; H, 5.26; N, 13.67.
1
-((1-(2-(2-(2-(2-(3-(Methoxyimino)-5-methyl-2-oxoindolin-
1
-yl)ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)
1
-((1-(2-(2-(2-(2-(3-(Methoxyimino)-5-methyl-2-oxoindolin-
1
indoline-2,3-dione (9e).
NMR (400 MHz, DMSO-d ) 2.29 (3H, s, CH ), 3.39–
Yellow solid, yield: 63%.
H
1
-yl)ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)
1
indoline-2,3-dione (9a). Brown oil, yield: 38%. H NMR
6
3
3
3
.45 (6H, m, 3 × ─CH ─), 3.49 (2H, t, ─CH ─),
(
400 MHz, DMSO-d ) 2.29 (3H, s, CH ), 3.36–3.44 (6H,
2
2
6
3
.64 (2H, t, ─CH ─), 3.74 (2H, t, ─CH ─), 3.83
m, 3 × ─CH ─), 3.48 (2H, t, ─CH ─), 3.68 (2H, t,
2
2
2
2
(
2H, t, ─CH ─), 4.24 (3H, s, NOMe), 4.45 (2H, t,
─
CH ─), 3.75 (2H, t, ─CH ─), 3.83 (2H, t, ─CH ─),
2
2
2
2
─
CH ─), 4.97 (2H, s, ─CH ─), 7.04–7.69 (7H, m,
4.21 (3H, s, NOCH ), 4.46 (2H, t, ─CH ─), 4.96 (2H, s,
2
2
3
2
Ar─H), 8.06 (1H, s, triazole-H). ESI-MS m/z: 599
CH ─), 7.05 (1H, d, Ar─H), 7.13 (1H, t, Ar─H), 7.21
2
+
[
M + Na] . Elemental Anal. Calcd (%) for C H
29 32
N O : C, 60.41; H, 5.59; N, 14.58; found: C, 60.33;
7
.63 (1H, t, Ar─H), 7.74 (1H, s, Ar─H), 8.11 (1H, s,
6 7
+
H, 5.52; N, 14.39.
triazole-H). ESI-MS m/z: 599 [M + Na] . Elemental
Anal. Calcd (%) for C H N O : C, 60.41; H, 5.59; N,
1
-(2-(2-(2-(2-(4-((3-(Hydroxyimino)-2-oxoindolin-1-yl)
methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)ethoxy)ethyl)-3-
methoxyimino)-5-methylindolin-2-one (9f).
2
9 32 6 7
1
4.58; found: C, 60.19; H, 5.37; N, 14.41.
(
Yellow solid,
1
-((1-(2-(2-(2-(2-(3-(Ethoxyimino)-5-methyl-2-oxoindolin-1-
1
yield: 57%. H NMR (400 MHz, DMSO-d ) 2.29 (3H, s,
yl)ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)
6
1
indoline-2,3-dione (9b). Brown oil, yield: 31%. H NMR
CH
─CH
3.85 (2H, t, ─CH
3
), 3.38–3.43 (6H, m, 3 × ─CH
─), 3.61 (2H, t, ─CH ─), 3.74 (2H, t, ─CH
─), 4.22 (3H, s, NOMe), 4.44 (2H, t,
2
─), 3.46 (2H, t,
(
400 MHz, DMSO-d ) 1.39 (3H, t, NOCH CH ), 2.27
2
2
─),
2
6
2
3
(
3H, s, CH ), 3.39–3.44 (6H, m, 3 × ─CH ─), 3.47 (2H,
2
3
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Design, Synthesis, and In Vitro Anti-Tumor Activities of 1,2,3-Triazole-
tetraethylene Glycol Tethered Heteronuclear Bis-Schiff Base Derivatives of Isatin
─
CH ─), 4.96 (2H, s, ─CH ─), 7.06 (2H, d, Ar─H), 7.16
3-(Ethoxyimino)-1-(2-(2-(2-(2-(4-((3-(ethoxyimino)-5-fluoro-
-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)
ethoxy)ethyl)-5-methylindolin-2-one (9j).
2
2
2
(1H, d, Ar─H), 7.21 (1H, d, Ar─H), 7.27 (1H, d, Ar─H),
Yellow solid,
7.39 (1H, d, Ar─H), 7.74 (1H, s, Ar─H), 7.88 (1H, s,
1
yield: 39%. H NMR (400 MHz, DMSO-d ) 1.40 (6H, t,
Ar─H), 8.10 (1H, s, triazole-H), 13.42 (1H, s, NOH).
ESI-MS m/z: 614 [M + Na] . Elemental Anal. Calcd (%)
for C H N O : C, 58.87; H, 5.62; N, 16.57; found: C,
6
+
2 × NOCH CH ), 2.29 (3H, s, ─CH ), 3.37–3.42 (6H,
2
3
3
m, 3 × ─CH ─), 3.46 (2H, t, ─CH ─), 3.63 (2H, t,
2
2
29 33 7 7
─
CH ─), 3.75 (2H, t, ─CH ─), 3.83 (2H, t, ─CH ─),
5
8.73; H, 5.47; N, 16.29.
2
2
2
3
-(Ethoxyimino)-1-(2-(2-(2-(2-(4-((3-(hydroxyimino)-2-
oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)
ethoxy)ethyl)-5-methylindolin-2-one (9g).
4.41–4.50 (6H, m, 2 × NOCH
CH
2
3
and ─CH
2
─), 4.98
(2H, s, ─CH ─), 7.06 (1H, d, Ar─H), 7.20 (1H, d,
2
Yellow solid,
yield: 44%. H NMR (400 MHz, DMSO-d ) 1.39 (3H, t,
Ar─H), 7.25 (1H, d, Ar─H), 7.30 (1H, d, Ar─H), 7.61
(1H, d, Ar─H), 7.69 (1H, d, Ar─H), 8.11 (1H, s,
1
6
+
NOCH CH ), 2.29 (3H, s, CH ), 3.38–3.42 (6H, m,
3
2
3
3
triazole-H). ESI-MS m/z: 674 [M + Na] . Elemental
× ─CH ─), 3.44 (2H, t, ─CH ─), 3.62 (2H, t,
Anal. Calcd (%) for C H FN O : C, 58.98; H, 5.88; N,
2
2
32
38
7 7
─CH ─), 3.74 (2H, t, ─CH ─), 3.83 (2H, t, ─CH ─),
2
2
2
15.05; found: C, 58.73; H, 5.67; N, 14.89.
4
.42–4.54 (4H, m, NOCH CH and ─CH ─), 4.96
2
3
2
(
2H, s, ─CH ─), 7.05 (2H, t, Ar─H), 7.16 (1H, d,
2
Ar─H), 7.22 (1H, d, Ar─H), 7.39 (1H, d, Ar─H), 7.71
1H, s, Ar─H), 7.94 (1H, d, Ar─H), 8.11 (1H, s,
triazole-H), 13.43 (1H, s, NOH). ESI-MS m/z: 628
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7
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4
5
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[
5
-Fluoro-3-(methoxyimino)-1-((1-(2-(2-(2-(2-(3-
methoxyimino)-5-methyl-2-oxoindolin-1-yl)ethoxy)ethoxy)
ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)indolin-2-one
(
[
1
(9h).
Yellow solid, yield: 71%. H NMR (400 MHz,
[
DMSO-d ) 2.28 (3H, s, ─CH ), 3.39–3.43 (6H, m,
6
3
[
3
× ─CH ─), 3.46 (2H, t, ─CH ─), 3.64 (2H, t,
2
2
─
CH ─), 3.73 (2H, t, ─CH ─), 3.83 (2H, t, ─CH ─),
2
2
2
[
4.26 (6H, s, 2 × NOMe), 4.43 (2H, t, ─CH ─), 4.96
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(
2H, s, ─CH ─), 7.03 (1H, s, Ar─H), 7.17–7.28 (3H, m,
2
Ar─H), 7.69–7.71 (2H, m, Ar─H), 8.10 (1H, s, triazole-
[
+
H). ESI-MS m/z: 646 [M + Na] . Elemental Anal. Calcd
(
%) for C H FN O : C, 57.78; H, 5.50; N, 15.72;
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7 7
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12] Wang, J. B.; Yun, D.; Yao, J. L.; Fu, W. T.; Huang, F. Y.;
3
-(Ethoxyimino)-1-(2-(2-(2-(2-(4-((5-fluoro-3-
(methoxyimino)-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-
[
yl)ethoxy)ethoxy)ethoxy)ethyl)-5-methylindolin-2-one (9i).
Yellow solid, yield: 53%. H NMR (400 MHz,
DMSO-d ) 1.40 (3H, t, NOCH CH ), 2.28 (3H, s,
─
─
3
NOCH CH and ─CH ─), 4.96 (2H, s, ─CH ─), 7.06–
7
Ar─H), 8.10 (1H, s, triazole-H). ESI-MS m/z: 660
[
C H FN O : C, 58.39; H, 5.69; N, 15.38; found: C,
5
Chen, L. P.; Wei, T. Eur J Med Chem 2018, 144, 493.
[13] Liang, C. Y.; Xia, J.; Lei, D.; Li, X.; Yao, Q. Z.; Gao, J. Eur J
Med Chem 2014, 74, 742.
1
6
2
3
[14] Gangarpu, K.; Manda, S.; Thota, S.; Yerra, R.; Karki, S. S.;
CH ), 3.36–3.42 (6H, m, 3 × ─CH ─), 3.45 (2H, t,
3
2
Balzarni, J.; Clercq, E. D.; Tokuda, H. Lett Drug Des Discov 2012, 9, 934.
[15] Ibrahim, H. S.; Abou-Seri, S. M.; Ismail, N. S. M.; Elaasser,
M. M.; Aly, M. H.; Abdel-Aziz, H. A. Eur J Med Chem 2016, 108, 415.
CH ─), 3.62 (2H, t, ─CH ─), 3.73 (2H, t, ─CH ─),
2
2
2
.85 (2H, t, ─CH ─), 4.24–4.50 (7H, m, NOMe and
2
[16] Pervez, H.; Ahmad, M.; Zaib, S.; Yaqub, M.; Naseer, M. M.;
2
3
2
2
Iqbal, J. MedChemComm 2016, 7, 914.
[17] Singh, A.; Nisha, B.; Bains, T.; Hahn, H. J.; Liu, N.; Tam, C.;
Cheng, L. W. MedChemComm 2017, 8, 1982.
.28 (4H, m, Ar─H), 7.64 (1H, d, Ar─H), 7.70 (1H, d,
+
[18] Xu, Y.; Guan, J. G.; Xu, Z.; Zhao, S. J. Fitoterapia 2018, 127, 383.
M
+
Na] . Elemental Anal. Calcd (%) for
[19] Hu, H. Q.; Song, X. F.; Fan, J. J Heterocyclic Chem 2018, 55, 265.
3
1
36
7
7
[20] Xue, H.; Zhang, G. F.; Zhang, D. Q.; Wu, Y. Q. J Heterocyclic
Chem 2018, 55, 1504.
8.19; H, 5.42; N, 15.13.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet